Antagonizing L-type Ca2+ channel reduces development of abnormal involuntary movement in the rat model of L-3,4-dihydroxyphenylalanine-induced dyskinesia.
BACKGROUND
Chronic L-3,4-dihydroxyphenylalanine (L-DOPA) treatment of Parkinson's disease (PD) leads to debilitating involuntary movements, termed L-DOPA-induced dyskinesia. Striatofugal medium spiny neurons (MSN) lose their dendritic spines and cortico-striatal glutamatergic synapses in PD and in experimental models of DA depletion. This loss of connectivity is triggered by a dysregulation of intraspine Cav1.3 L-type Ca2+ channels. Here we address the possible implication of DA denervation-induced spine pruning in the development of L-DOPA-induced dyskinesia.


METHODS
The L-type Ca2+ antagonist, isradipine was subcutaneously delivered to rats at the doses of .05, .1, or .2 mg/kg/day, for 4 weeks, starting the day after a unilateral nigrostriatal 6-hydroxydopamine (6-OHDA) lesion. Fourteen days later, L-DOPA treatment was initiated.


RESULTS
Isradipine-treated animals displayed a dose-dependent reduction in L-DOPA-induced rotational behavior and abnormal involuntary movements. Dendritic spine counting at electron microscopy level showed that isradipine (.2 mg/kg/day) prevented the 6-OHDA-induced spine loss and normalized preproenkephalin-A messenger RNA expression. Involuntary movements were not reduced when isradipine treatment was started concomitantly with L-DOPA.


CONCLUSIONS
These results indicate that isradipine, at a therapeutically relevant dose, might represent a treatment option for preventing L-DOPA-induced dyskinesia in PD.
Schuster
Stefan
S
Boehringer Ingelheim Pharma GmbH & Company KG, Biberach, Germany.
Doudnikoff
Evelyne
E
Rylander
Daniella
D
Berthet
Amandine
A
Aubert
Incarnation
I
Ittrich
Carina
C
Bloch
Bertrand
B
Cenci
M Angela
MA
Surmeier
D James
DJ
Hengerer
Bastian
B
Bezard
Erwan
E
D000818:Animals; D002121:Calcium Channel Blockers / Q000008:administration & dosage / Q000494:pharmacology*; D020746:Calcium Channels, L-Type / Q000187:drug effects*; D054022:Cerebrum / Q000378:metabolism / Q000648:ultrastructure; D049229:Dendritic Spines / Q000187:drug effects / Q000648:ultrastructure; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D004409:Dyskinesia, Drug-Induced / Q000378:metabolism / Q000517:prevention & control*; D004745:Enkephalins / Q000378:metabolism; D017275:Isradipine / Q000008:administration & dosage / Q000494:pharmacology / Q000627:therapeutic use*; D007980:Levodopa / Q000009:adverse effects* / Q000494:pharmacology; D008297:Male; D009043:Motor Activity / Q000187:drug effects; D009553:Nimodipine / Q000494:pharmacology; D016627:Oxidopamine; D011498:Protein Precursors / Q000378:metabolism; D012333:RNA, Messenger / Q000378:metabolism; D051381:Rats; D017208:Rats, Wistar; D013565:Sympatholytics / Q000008:administration & dosage*
D002121:Calcium Channel Blockers; D020746:Calcium Channels, L-Type; D004745:Enkephalins; D011498:Protein Precursors; D012333:RNA, Messenger; D013565:Sympatholytics; D007980:Levodopa; D009553:Nimodipine; D016627:Oxidopamine; C033660:preproenkephalin; D017275:Isradipine